PROJECT SUMMARY Zika virus (ZIKV) is the cause of an ongoing, worldwide epidemic. While mosquitos are the main vector of transmission, studies have shown that ZIKV can be spread between humans through sexual contact. ZIKV infection generally causes a mild, self-resolving illness in most immunocompetent adults. However, infection in pregnant women can lead to devastating outcomes. Epidemiological studies have linked ZIKV infection with a rise in microcephaly cases in Brazil, and subsequent studies in animal models have shown that congenital infection with ZIKV, either through a subcutaneous or intravaginal route, causes microcephaly and other severe birth defects. Vaccine efforts have focused on preventing infection by mosquito bite, and recent studies have uncovered specific antibody epitopes that can protect against the virus. However, it is unclear whether these vaccines and immune correlates will be effective in protecting against sexually transmitted infection (STI). Vaccine design against viral STIs has proven to be difficult and currently, only human papilloma virus (HPV) infection can be prevented by vaccination. Most vaccines depend on generating robust circulating immunity for protection. However, circulating immunity may not be sufficient to protect against viral STIs; rather, tissue-specific immunity may be required. In this proposal, we will use an in vivo model of intravaginal ZIKV infection to determine whether conventional vaccination platforms are sufficient to protect against sexual transmission of ZIKV. We will assess the immune response against intravaginal and subcutaneous ZIKV infection within the female reproductive tract (FRT), identify the components of the primary immune response that are required for controlling infection using genetic mouse models and examine the establishment of local immunity in the FRT. We will then determine whether prior exposure to ZIKV through a subcutaneous route protects against subsequent sexual exposure to ZIKV. Finally, we will test the protective capacity of a conventional vaccine administered through commonly used immunization routes against intravaginal ZIKV infection. We will identify the components of the immune response that are required for protection and determine whether conventional vaccines can establish tissue-resident immunity in the FRT. Together, these studies will reveal the requirements for protection against sexual transmission of ZIKV and determine whether current vaccines that are being tested against ZIKV are sufficient to protect against sexually transmitted ZIKV infection.